Neurodegeneration occurs when there is a progressive and age-dependent loss in the structure or function of neurons. Recent research has revealed similarities on the molecular level across various neurodegenerative diseases, such as accumulation and aggregation of misfolded proteins and mitochondrial dysfunction. Such pathogenic mechanisms are best studied in diseases caused by mutations in genes involved in these common pathways. Examples of this concept are mutations in lysosomal proteins that lead to lysosomal dysfunction and neurodegeneration in various conditions across the lifespan.
Lysosomes and Rare Lysosomal Diseases
Lysosomes serve as recycling organelles in neurons. They remove debris and toxic waste that accumulate in neurons during normal and pathological neuronal activity. When lysosomes do not work at sufficient capacity to remove misfolded proteins and dysfunctional organelles, neurons accumulate and store these toxic products that in turn lead to neurodegeneration. Primary lysosomal dysfunction in diseases of the developing nervous system is well known; but the link between defective lysosomal proteins and adult onset neurodegenerative diseases is only now being recognized.
More than 50 lysosomal storage diseases (LSDs) are classified according to the nature of the accumulating substrate and neurodegeneration in the central nervous system is a common feature of these diseases. With severe debilitating impairment, the signs of this disease are usually developmental and systemic. Early death may occur before the slowly-developing neurodegenerative disease becomes truly apparent (1, 3, 4).
Recent clinical and genetic evidence has identified an interesting link between LSDs and more common forms of neurodegeneration such as Parkinson’s disease. For example, patients with Gaucher’s diseases (lysosomal storage disease) are at higher risk of developing PD and patients with PD are more likely carriers of mutations in glucocecerebrosidase that causes Gaucher’s disease. In our recent work, we found that glucocerebrosidase can serve as target for development of new therapies in PD (2, 4).
Center for Rare Neurological Diseases' Approach
Taken together, these observations suggest that neurodegenerative traits seem more likely to develop from milder forms of lysosomal dysfunction, and their emergence may be the result of aging neurons. We propose, therefore, that lysosomal disorders are a continuum of diseases across the lifespan and the development of new therapies to increase lysosomal function will be beneficial in the treatment of neurodegenerative disorders. Focusing on rare lysosomal diseases, we plan to identify specific targets and mechanisms that contribute to neurodegeneration. It is expected that such defined targets will facilitate mechanism-based therapeutic development for neurodegenerative disorders that affect children and adults.
Learn more about current community knowledge, and how it informs the center’s position and approach via the links below.
- Lysosomal Storage Diseases Accumulate Aggregation-prone Proteins
- Convergence of Lysosomal and Mitochondrial Pathways in Neurodegeneration
Following is a list of publications referenced in the development of our position and approach.
- Nixon RA, Yang DS, Lee JH. Neurodegenerative lysosomal disorders: a continuum from development to late age. Autophagy. 2008 Jul; 4(5):590-9. Epub 2008 May 12. PMID: 18497567
- Mazzulli, J.R., Sun, Y., Knight, A.L., McLean, P.J., Caldwell, G, Sidransky, E, Grabowski, G.A. and Krainc, D. Gaucher’s Disease Glucocerebrosidase and alpha-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell. 2011 Jul 8;146(1):37-52. (Accompanied by the Perspective in Cell, Science Translational Medicine, and Editors’ Choice in Science) PMID: 21700325
- Bellettato CM, Scarpa M. Pathophysiology of neuropathic lysosomal storage disorders. J Inherit Metab Dis. 2010 Aug;33(4):347-62. PMID: 20429032
- Shachar T, Lo Bianco C, Recchia A, Wiessner C, Raas-Rothschild A, Futerman AH. Lysosomal storage disorders and Parkinson's disease: Gaucher disease and beyond. Mov Disord. 2011 Aug 1;26(9):1593-604. PMID: 21618611
Learn how we are applying our knowledge to our research.